Bis(sulfide)gold(1+) salts

ABSTRACT

The compounds are bis(sulfide)gold(1+) salts which have antiarthritic activity.

This invention relates to new bis(sulfide)gold(1+) salts. Thesecompounds have antiarthritic activity and, in particular, are of use inthe treatment of rheumatoid arthritis.

The compounds of this invention are represented by the followingformula: ##STR1## in which R₁ and R₂ are 2-hydroxyethyl or takentogether with the sulfur atom to which they are attached form atetrahydrothienyl or tetrahydrothiapyranyl ring and X is a weaklynucleophilic anion.

A particular compound of this invention is represented by Formula I inwhich R₁ and R₂ taken together with the sulfur atom to which they areattached form a tetrahydrothienyl ring.

The anion X in Formula I is a weakly nucleophilic anion such as, forexample, perchlorate (ClO₄), iodate (IO₄), tetrafluoroborate (BF₄) andhexafluorophosphate (PF₆).

The compounds of this invention are prepared by the following procedure:##STR2## The terms R₁, R₂ and X are as defined above.

According to the above procedure, a sulfide, R₁ R₂ S, is reacted withgold acid chloride trihydrate to give the chloro(sulfide)gold compoundR₁ R₂ SAuCl. This reaction is carried out in a suitable solvent, such asaqueous ethanol, conveniently at room temperature. Thechloro(sulfide)gold compound is reacted with a silver salt AgX or asodium salt NaX and a sulfide R₁ R₂ S. This reaction is carried out in asolvent, such as acetone, at room temperature. The products are thebis(sulfide)gold(1+) salts of this invention.

The compounds of this invention are useful in treatment of arthritis.This activity is demonstrated by the following test procedures.

Inhibition of adjuvant induced polyarthritis in rats, as measured byreduction of rat paw edema, is produced by compounds of this inventionat daily oral doses of about 20 mg./kg. (calculated on gold content). Inthis test procedure, adjuvant arthritis in rats is produced by a singleintradermal injection of 0.75 mg. of Mycobacterium butyricum suspendedin white paraffin oil into the left hindpaw footpad. The injected pawbecomes inflamed (increased volume) and reaches maximal size within 3 to5 days (primary lesion). The animals exhibit a decrease in body weightgain during the initial period. The adjuvant arthritis (secondarylesion) occurs after approximately ten days and is characterized byinflammation of the non-injected right hind leg, decrease in bodyweight, and further increase in the volume of the injected left hindleg. Test compounds are administered daily, beginning on the day of theadjuvant injection, for 17 days thereafter, exclusive of days 4, 5, 11and 12. Antiarthritic activity is shown by the ability to inhibit thedevelopment of either primary or secondary lesions of adjuvantarthritis.

The compounds of this invention are administered in conventional dosageforms prepared by combining a compound of Formula I in an amountsufficient to produce antiarthritic activity with standardpharmaceutical carriers according to conventional procedures. Theseprocedures may involve mixing, granulating and compressing or dissolvingthe ingredients as appropriate to the desired preparation. The resultingpharmaceutical compositions are also objects of this invention. Oraldosage forms are preferred.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glyceryl monostearateor glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 1 mg. to about 10 mg.

The method of producing antiarthritic activity by administeringinternally to an animal a compound of Formula I is also an object ofthis invention. The compounds of Formula I are administered in an amountsufficient to produce antiarthritic activity. The route ofadministration may be orally or parenterally, preferably orally.Advantageously, doses will be administered 1 or 2 times a day, with thedaily dosage regimen being preferably from about 1 mg. to about 12 mg.When the method is carried out as described above, antiarthriticactivity is produced.

One skilled in the art will recognize that in determining the amounts ofthe active ingredient in the claimed compositions and used in theclaimed methods, the activity of the chemical ingredient as well as thesize of the host animal must be considered.

The following examples are not limiting but are illustrative of theinvention.

EXAMPLE 1

A solution of 4.0 g. (0.045 mole) of tetrahydrothiophene in 15 ml. ofethanol was added dropwise to a solution of 5.0 g. (0.013 mole) of goldacid chloride trihydrate in 15 ml. of distilled water maintained at roomtemperature. After stirring 15 minutes, the precipitate was removed byfiltration, washed with water, then ethanol and finally ether.Crystallization from ethanol gave chloro(tetrahydrothienyl)gold(I), m.p.148°-150° C.

A solution of 0.87 g. (0.004 mole) of silver perchlorate in 15 ml. ofacetone was added dropwise to a mixture of 1.32 g. (0.004 mole) ofchloro(tetrahydrothienyl)gold(I) and 2 ml. of tetrahydrothiophene in 30ml. of acetone and 5 ml. of methylene chloride. After stirring for 30minutes, the precipitate was removed by filtration and the solventremoved at reduced pressure to give an oil. The oil was washed withether and the ether layer decanted. The resultant oil was dissolved inmethylene chloride, filtered and the solvent removed at reduced pressureto give bis(tetrahydrothienyl)gold(1+) perchlorate, m.p. 114°-120° C.

EXAMPLE 2

By the procedure of Example 1, tetrahydrothiapyran is reacted with goldacid chloride trihydrate to give chloro(tetrahydrothiapyranyl)gold(I).

Adding an acetone solution of silver perchlorate to a mixture ofchloro(tetrahydrothiapyranyl)gold(I) and tetrahydrothiapyran in acetoneand methylene chloride, stirring the resulting mixture for 30 minutes,then working up by the procedure of Example 1 givesbis(tetrahydrothiapyranyl)gold(1+) perchlorate.

Using silver iodate in the above procedure in place of silverperchlorate gives bis(tetrahydrothiapyranyl)gold(1+) iodate.

EXAMPLE 3

Using silver tetrafluoroborate in place of silver perchlorate in theprocedure of Example 1, the product is bis(tetrahydrothienyl)gold(1+)tetrafluoroborate.

Similarly, using silver hexafluorophosphate, the product isbis(tetrahydrothienyl)gold(1+) hexafluorophosphate.

EXAMPLE 4

6.2 Grams (0.051 mole) of di(2-hydroxyethyl)sulfide was added to 10 g.(0.025 mole) of gold acid chloride trihydrate in 100 ml. of ethanol at25° C. After one hour, the solvent was removed at reduced pressure. Theresultant oil was dissolved in acetone and chromatographed over silicagel (acetone) to give chloro[di(2-hydroxyethyl)sulfide]gold(I) as anorange oil.

A solution of 2.28 g. (0.011 mole) of silver perchlorate in 70 ml. ofacetone is added to a solution of 4.0 g. (0.011 mole) ofchloro[di(2-hydroxyethyl)sulfide]gold(I) and 5 ml. ofdi(2-hydroxyethyl)sulfide in 80 ml. of acetone. After stirring for 30minutes at room temperature, the mixture is filtered and the solventremoved at reduced pressure. The residue is dissolved in methylenechloride, filtered and the solvent removed at reduced pressure to givebis[di(2-hydroxyethyl)sulfide]gold(1+) perchlorate.

EXAMPLE 5

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        bis(tetrahydrothienyl)gold(1+) perchlorate                                                              5 mg.                                               magnesium stearate        5 mg.                                               lactose                   200 mg.                                             ______________________________________                                    

The above ingredients are screened, mixed and filled into a hard gelatincapsule.

The capsules are administered orally to subjects in need ofantiarthritic treatment in amounts within the daily dose range givenhereabove.

Similarly, the outer gold compounds of Formula I may be formulated intocapsules by the procedure of Example 5.

Other pharmaceutical compositions such as tablets containing a compoundof Formula I as the active ingredient are formulated by standardprocedures.

What is claimed is:
 1. A compound of the formula: ##STR3## in which R₁and R₂ taken together with the sulfur atom to which they are attachedform a tetrahydrothienyl or tetrahydrothiapyranyl ring and X is a weaklynucleophilic anion selected from perchlorate, iodate, tetrafluoroborateor hexafluorophosphate.
 2. A compound of claim 1 in which R₁ and R₂taken together with the sulfur atom to which they are attached form atetrahydrothienyl ring.
 3. A pharmaceutical composition havingantiarthritic activity, in dosage unit form, comprising a pharmaceuticalcarrier and a compound of claim
 1. 4. A method of producingantiarthritic activity which comprises administering internally to ananimal a compound of claim 1.